leukotriene-d4 and Rhinitis--Allergic--Perennial

To investigate the changes of leukotriene D4 (LTD4) in nasal discharge and plasma of patients with persistent allergic rhinitis (AR) and the effects of antihistamine.. The investigation was a prospective, randomized controlled trial. Forty AR patients (group C) were divided randomly into two subgroup. One group received oral antihistamine 10 mg everyday for one week (group CA) and another group received no loratadine tablets 10 mg everyday for one week (group CB). Fifteen age matched healthy (group D) people were enrolled as control. The level of LTD4 and interleukin-5 (IL-5) in both nasal discharge and plasma by using enzyme linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), cell counts and cell differentials in nasal discharge, were measured before and after three month. The clinical symptom and life quality scores of group C were also investigated.. The concentrations of LTD4 in nasal discharge [(794 +/- 305) pg] and plasma [(5219 +/- those in group D [(347 +/- 169) pg, (2283 +/- 489) ng/L, all P 1185) ng/L] in group C were significantly higher than those in group D [(347 +/- 169) pg, (2283 +/- 489) ng/L, all P < 0.05]. The level of LTD4 in nasal discharge was positively correlated with the percentage of neutrophil (r = 0.453, P < 0.05) and IL-5 (r = 0.364, P < 0.05). The pre- and post-therapy concentrations of nasal discharge and plasma in group CA were (812 +/- 1592) pg, (657 +/- 495) pg and (5422 +/- 935) ng/L, (4589 +/- 1057) ng/L respectively; While in group CB the concentrations were (776 +/- 227) pg, (860 +/- 194) pg and (5074 +/- 1850) ng/L, (6063 +/- 450) ng/L, respectively. There were no significant difference either in the level of LTD4 in nasal discharge or in plasma in both groups (all P > 0.05).. The results suggested that LTD4 was involved in airway inflammation in AR. Antihistamine was not effective enough in decreasing the levels of LTD4 in both nasal discharge and plasma of AR patients.

Topics: Adult; Anti-Allergic Agents; Bodily Secretions; Female; Histamine H1 Antagonists; Humans; Leukotriene Antagonists; Leukotriene D4; Male; Middle Aged; Plasma; Prospective Studies; Rhinitis, Allergic, Perennial

One possible mechanism of the nasal obstruction observed in allergic rhinitis is thought to be a dilatation of veins in nasal mucosa, although the exact mechanism(s) is not fully understood. An involvement of cysteinyl leukotrienes (CysLTs) in the nasal obstruction has also been suggested. In addition to the specific antigen-induced nasal symptoms, nasal hyperresponsiveness to non-specific stimuli is one of the characteristic features of patients with allergic rhinitis. Augmentation of LTD(4)-induced venodilatation (a part of nasal hyperresponsiveness) of nasal mucosae in antigen-challenged rats was investigated. The LTD(4)-induced venodilatation was significantly increased in antigen-challenged rats, although venodilatation by application of LTD(4) was not induced in nasal mucosae of control rats. The LTD(4)-induced venodilatation was significantly inhibited by pretreatment with L-NMMA [an inhibitor of nitrix oxide synthase (NOS)]. Although mRNA of CysLT1 receptor of nasal mucosa was within control level, the LTD(4)-induced production of NOx in nasal cavity was augmented in repeatedly antigen challenge rats. In addition, the level of iNOS mRNA was also significantly augmented in nasal mucosae of repeatedly antigen-challenged rats. Interestingly, sodium nitroprusside (SNP; an NO donor)-induced venodilatation itself was significantly augmented in nasal mucosae of repeatedly antigen challenge rats. In conclusion, we here suggest that the sensitivity of venodilatation to LTD(4) was augmented in nasal mucosae of challenged rats. Therein, not only increased NO production but also enhanced NO responsiveness might be involved in the development of nasal hyperresponsiveness in allergic rhinitis.

Topics: Animals; Antigens; Cysteine; Leukotriene D4; Leukotrienes; Male; Nasal Mucosa; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; omega-N-Methylarginine; Rats; Rats, Wistar; Receptors, Leukotriene; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; RNA, Messenger; Vasodilation

Topics: Aspirin; Drug Hypersensitivity; Enzyme-Linked Immunosorbent Assay; Humans; Leukocytes; Leukotriene C4; Leukotriene D4; Leukotriene E4; Rhinitis, Allergic, Perennial; Sensitivity and Specificity; Sinusitis

We examined whether nasal hyperresponsiveness to leukotriene (LT) D4 is seen in our allergic rhinitis model, which showed sneezing and biphasic nasal blockage by repeated antigen inhalation challenge, and whether a dilatation of mucosal blood vessels contributes to this hyperresponsiveness. Nasal blockage [increase of specific airway resistance (sRaw)] was indexed as nasal (hyper)responsiveness. The sensitized-challenged guinea pig showed a remarkable dose-dependent increase in sRaw by intranasal instillation of LTD4 (10 microl/nostril) at 10(-10) to 10(-6) M 10 h and 2 days but not 7 days after the challenge. The increase in sRaw induced by LTD4 was largely blocked by pranlukast or naphazoline, and this was dose-dependently suppressed by N(omega)-nitro-L-arginine methyl ester. Sodium nitroprusside induced an elevation of sRaw in the sensitized-challenged animal in the hyperresponsiveness state, but the degree did not differ from that in the non-sensitized-non-challenged group. The amount of NO2- and NO3- in nasal cavity lavage fluid after LTD4 instillation in the sensitized-challenged animal in the hyperresponsiveness state was significantly greater than that before the instillation. These results demonstrate that the hyperresponsiveness to LTD4 acquired by repeated antigen challenge is mainly due to dilatation of nasal blood vessels, which can be related to hyperproduction of nitric oxide through cysteinyl LT1-receptor activation.

Topics: Airway Resistance; Allergens; Animals; Disease Models, Animal; Guinea Pigs; Leukotriene D4; Male; Nasal Mucosa; Nasal Obstruction; Pollen; Rhinitis, Allergic, Perennial; Vasodilation

The in vivo model of nasal microvascular leakage was used for the nasal allergic challenge in ovalbumin (OA)-sensitized guinea pigs, or nasal stimulation with leukotriene D4 (LTD4) in non-sensitized animals. An intravenous injection of Evans blue dye was given as an index of nasal microvascular leakage. Following the nasal stimulation with LTD4, the concentration of dye in the nasal lavage fluid rapidly increased. Oral administration of ONO-1078 (pranlukast) (3-30 mg/kg) significantly inhibited the LTD4-induced nasal microvascular leakage. In OA-sensitized guinea pigs, the excretions of dye into nasal lavage fluid were recognized soon after the topical antigenic stimulation and continued for over 60 minutes. Oral administration of ONO-1078 (30 mg/kg) significantly inhibited the antigen-induced microvascular leakage. These results suggest that ONO-1078 may be of therapeutic use for nasal allergy.

Topics: Animals; Anti-Asthmatic Agents; Chromones; Disease Models, Animal; Guinea Pigs; Leukotriene Antagonists; Leukotriene D4; Male; Membrane Proteins; Ovalbumin; Receptors, Leukotriene; Rhinitis, Allergic, Perennial

To examine whether cysteinyl leukotrienes (cysLTs: LTC4, LTD4 and LTE4) induce symptoms of allergic rhinitis via their receptors, we studied the following: i) the specific binding of radiolabeled cysLTs to guinea pig nasal mucosa membrane and ii) effects of nasal LTD4 challenge in normal guinea pigs. The binding study indicated that there was a single population of binding sites for LTC4, LTD4 and LTE4 with Kd and Bmax values of 34.9+/-2.0, 0.252+/-0.015 and 0.589+/-0.039 nM and 10, 140+/-490, 122+/-11 and 306+/-23 fmol/mg protein, respectively. The in vivo study showed that topical nasal challenge of LTD4 (0.1-30 microg/nose) increased nasal secretion, nasal airway resistance and nasal eosinophil infiltration without inducing sneezing. While the increases in nasal secretion and nasal airway resistance were transient, peaking 10 to 20 min after LTD4 challenge, nasal eosinophil infiltration persisted at least until 24 hr post-challenge. These nasal symptoms were dose-dependently suppressed by oral administrations of pranlukast (0.3-3 mg/kg). The results suggest that cysLTs cause not only early-phase symptoms but also nasal eosinophil migration, a characteristic associated with the late-phase symptom of allergic rhinitis, via a receptor-mediated mechanism. Cysteinyl leukotrienes, thus, may be important mediators in allergic rhinitis.

Topics: Administration, Oral; Airway Resistance; Animals; Anti-Asthmatic Agents; Binding Sites; Chromones; Dose-Response Relationship, Drug; Eosinophils; Guinea Pigs; In Vitro Techniques; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Male; Nasal Mucosa; Receptors, Leukotriene; Rhinitis, Allergic, Perennial; Tritium

The effects of topically administered substance P (SP) on nasal blood flow and nasal airway resistance (NAR) were evaluated in 11 subjects with perennial nasal allergy. The change in NAR induced by SP was compared with those induced by nasal challenge with histamine, leukotriene D4 (LTD4), and antigen. In doses > or = 16 nmol, SP caused a significant increase of nasal blood flow within 5 minutes that lasted for less than 20 minutes. In doses > or = 16 nmol, SP caused a dose-dependent, short-lasting, significant increase in NAR. The magnitude of the increase in NAR was LTD4 > SP > histamine when compared on a molar basis. Our results may suggest that SP released from C fiber terminals is partially involved in an early nasal vascular response after antigen challenge by acting on adjacent vascular smooth muscle to cause a transient vasodilatation of both resistance and capacitance vessels only while sensory stimulation persists in subjects with nasal allergy.

Topics: Adolescent; Adult; Airway Resistance; Antigens; Female; Histamine; Humans; Leukotriene D4; Male; Nasal Mucosa; Rhinitis, Allergic, Perennial; Substance P